In this project we will conduct a clinical trial in patients with relapsed B cell and T cell lymphomas. It is based on a new method of therapeutic vaccination for lymphoma, which we developed in murine models. In mice, advanced systemic tumors can be temporarily eliminated by inducing tumor cell death by chemotherapy. In contrast, long-term tumor elimination is achieved by chemotherapy followed by local intralesional injection of either dendritic cells or a CpG oligonucleotide, an activator of resident dentritic cells (in situ vaccination). Either maneuver alone, cell death induction or intralesional injection, has no long-term effect. The combination results in uptake and processing of tumor antigens by the dendritic cells and subsequent induction of a systemic T cell immune response which is capable of eliminating tumor at distant sites. In the clinical trial, local tumor death will be induced by low dose radiotherapy and CpG will be injected into the same local lesion. Patients will be monitored for anti tumor immune responses and for tumor regression at distant sites. Direct signaling effects of CpG oligonucleotides on the human tumors will be studied in collaboration with Dr. Nolan in Project 2, and related to the clinical effects seen in patients. We are fortunate to have available for these studies a clinical grade CpG compound which has already been safety tested, which has proven to be effective in humans as a vaccine adjuvant and which has shown preliminary evidence of anti tumor efficacy in trials at Stanford in patients with cutaneous T cell lymphoma. In parallel with these clinical trials we will further develop the maneuver of in situ vaccination in animal models by studying its mechanism and by combining immunostimulatory agents to optimize their anti tumor effects. Lessons learned from the animal model will be translated into the design of future clinical trials.